MasquEradErs oF nonalCoholiC Fatty livEr disEasE

Chair
Rohit Kohli, MBBS, MS
Associate Professor of Pediatrics
Medical Director, Complex Surgery and
Transplant Inpatient Unit
Co-Director, Steatohepatitis Center
Cincinnati Children’s Hospital Medical Center
Cincinnati, OH
Masqueraders of
Nonalcoholic Fatty Liver Disease
Faculty
Ruba K. Azzam, MD
Associate Professor of Pediatrics
Medical Director, Pediatric Liver Transplant Program
University of Chicago
Comer Children’s Hospital
Chicago, IL
A CME Case-Based Newsletter
Regino P. Gonzalez-Peralta, MD
Professor of Pediatrics
Assistant Dean, Office of Diversity and Health Equity
University of Florida College of Medicine
Gainesville, FL
Maureen Jonas, MD
Clinical Director, Hepatology
Medical Director, Liver Transplant Program
Boston Children’s Hospital
Professor of Pediatrics
Harvard Medical School
Boston, MA
CME Content Reviewer
Henry Lin, MD
Attending Physician
The Children’s Hospital of Philadelphia
Philadelphia, PA
Medical Writer
Matt Kilby
Science Writer
Jointly sponsored by NASPGHAN and The NASPGHAN
Foundation for Children’s Digestive Health and Nutrition.
Release Date: June 1, 2014, Expiration Date: May 31, 2017
2.0 AMA PRA Category 1 CME CreditsTM
Jointly sponsored by NASPGHAN and The NASPGHAN
Foundation for Children’s Digestive Health and Nutrition.
This educational activity is supported by an independent
medical education grant from Synageva.
Introduction
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in
the United States, affecting an estimated 10%–46% of the US population and
somewhere between 3% and 25% of children. Obesity is the most common cause
of NAFLD; however, 3%–10% of pediatric patients with NAFLD are nonobese. It
is important to understand potential causes of NAFLD that are not obesity related
to avoid misdiagnosis in pediatric patients. These include but are not limited to
mitochondrial hepatopathies, kwashiorkor/anorexia nervosa, Wilson’s disease,
cholesteryl ester storage disease (CESD)/lysosomal acid lipase (LAL) deficiency,
hepatitis C, uncontrolled type 1 diabetes, and mitochondrial disorders.
identified conflicts of interest, the educational content was peer-reviewed by a
physician member of the NASPGHAN Review Committee who has nothing to
disclose. The resulting certified activity was found to provide educational content
that is current, evidence-based, and commercially balanced. Disclosure of Unlabeled or Investigational Drugs
This educational activity may contain discussion of published and/or investigational
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opinions expressed in the educational activity are those of the faculty. Please refer
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Physicians must recognize clues that fatty liver might not be the typical obesityassociated NAFLD. The real-life cases presented here illustrate these clinical clues
and help providers decide which patients should have additional testing, as
well as which tests should be considered. Once proper diagnoses are made,
the cases also consider appropriate treatment approaches for patients with these
“masqueraders of NAFLD.”
Medium or Combination of Media Used
This activity will consist of a mailed or Web-based monograph and a posttest. This
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Target Audience
This activity is designed for pediatricians, pediatric gastroenterologists and hepatologists, primary care physicians, physician assistants, nurse practitioners, and
other health care professionals who treat patients at risk for NAFLD.
How to Receive CME Credit:
To receive CME credit for reviewing this activity, participants must review
the CME information (learning objectives, disclosures, etc.), review the entire
activity, and complete the activity posttest and evaluation questions.
Learning Objectives
Participants completing this activity should be better able to:
•Recognize disease types of NAFLD in nonobese pediatric patients, such as
Wilson’s disease, lysosomal acid lipase deficiency, and Alpers syndrome
•Describe the pathophysiology of NAFLD disease types in nonobese pediatric
patients, including disease definitions and causes
•Describe recommended strategies for diagnosing different types of NAFLD in
nonobese pediatric patients
•Describe appropriate and evidence-based treatments for NAFLD in nonobese
pediatric patients
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Certificates will be provided immediately after completion of both the
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Rohit Kohli, MBBS, MS was on Synageva’s speakers bureau and
relationship has ended.
Ruba K. Azzam, MD has nothing to disclose.
Regino P. Gonzalez-Peralta, MD has received honoraria from
Synageva.
Maureen Jonas, MD has nothing to disclose
Henry Lin, MD has nothing to disclose
Matt Kilby has nothing to disclose.
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2
© Copyright 2014 NASPGHAN and The NASPGHAN Foundation for Children’s Digestive Health and Nutrition.
Introduction
Nonalcoholic fatty liver disease (NAFLD) is the most common
liver disease in the United States, affecting an estimated
10%–46% of the US population1–3 and somewhere between
3% and 25% of children.3–5 Obesity is the most common
cause of NAFLD; however, 3%–10% of pediatric patients
with NAFLD are nonobese.6–9 It is important to understand
potential causes of NAFLD that are not obesity related to
avoid misdiagnosis in pediatric patients. These include
but are not limited to mitochondrial hepatopathies,
kwashiorkor/anorexia nervosa, Wilson’s disease,
cholesteryl ester storage disease (CESD)/lysosomal
acid lipase (LAL) deficiency, hepatitis C, uncontrolled
type 1 diabetes, and mitochondrial disorders.
Physicians must recognize clues that fatty liver might
not be the typical obesity-associated NAFLD. The
real-life cases presented here illustrate these clinical
clues and help providers decide which patients should
have additional testing, as well as which tests should be
considered. Once proper diagnoses are made, the cases
also consider appropriate treatment approaches for patients
with these “masqueraders of NAFLD.”
Case Study 1: Javier
Javier is a 13-year-old Hispanic boy referred for evaluation
of liver test abnormalities. He was diagnosed with
hypothyroidism (and started on levothyroxine) approximately
1 year ago, when laboratory testing for fatigue showed
elevated thyroid-stimulating hormone (TSH). At the time, he
also had elevated aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) levels (greater than twice the
upper limit of normal), which persisted on several subsequent
determinations. Other than experiencing mild, vague, and
intermittent right upper quadrant abdominal pain over the
preceding 3 days, he is completely asymptomatic. There
are no lung, liver, or neurological complaints. His mother has
hypothyroidism; no relatives have liver, lung, neurological, or
psychiatric disease.
The weight is 69 kg (>95%), the height is 162 cm (60%),
and the body mass index (BMI) is 26 kg/m2 (>95%). He has
abdominal striae. Neither the liver nor spleen is enlarged,
and there are no stigmata of chronic liver disease. Results
of complete blood count (CBC), prothrombin time, TSH,
and liver tests are normal except for elevated AST and ALT
(132 and 120 IU/L, respectively). Liver-specific tests, including
antinuclear, smooth muscle, and liver-kidney microsomal
antibodies; hepatitis A and C serology; hepatitis B surface
antigen; creatinine kinase; and alpha 1 antitrypsin level and
Pi phenotype are normal; the ceruloplasmin concentration is
low (8 mg/dL [normal > 20 mg/dL]); and there is borderline
hepatomegaly on abdominal sonogram with increased
echogenicity consistent with fatty infiltration of the liver.
3
Wilson’s Disease
In most cases, Wilson’s disease presents clinically as either a
liver, neurological, or psychiatric disorder.10,12 In children, liver
dysfunction is the most common initial presenting scenario,
occurring in 50% of affected pediatric patients under age
18 years and 75% under age 10 years. Copper toxicity is rarely
evident before ages 3–5 years, and manifestations include
asymptomatic elevations of transaminases, acute or chronic
hepatitis, cirrhosis, and acute liver failure. Neurological or
psychiatric signs are the first indication of illness in 40%–45%
of patients with Wilson’s disease and have been recorded in
children as young as age 6 years. Neurological symptoms
include tremors, drooling, poor coordination, ataxia, writing
difficulties, dementia, anxiety or depression, psychosis, and
schizophrenia.
Pathophysiology
Wilson’s disease is an autosomal recessive disease that
affects 3–30 in every 1 million individuals.10–12 It is caused
by mutation in the ATP7B gene, which encodes a metaltransporting adenosine triphosphatase that aids in the
transmembrane transport of copper.10,13–16 Alterations in ATP7B
protein function leads to copper accumulation in the liver and
results in injury as excess copper is released into the blood
and deposited in various organs, including the brain, cornea,
heart, kidneys, and pancreas.
The original clinical description of Wilson’s disease was in
a group of patients between ages 5 and 40 years with
necrotic damage in lenticular nuclei and liver cirrhosis.17 Later
descriptions included neurologic manifestations and KayserFleischer (KF) rings—copper deposition in the cornea that
appears as a ring of golden brownish pigment near the
limbus.10,18 An important biochemical feature of Wilson’s
disease is decreased serum ceruloplasmin concentration.10,19
Diagnosis
Patients with Wilson’s disease may present with vague, mild,
and varied symptoms that can make diagnosis challenging.10,20
Because no single conclusive test exists to detect or exclude
Wilson’s disease, clinical findings and biochemical testing need
to be incorporated to establish a firm diagnosis (Figure 1).
Figure 1. Diagnostic Approach to Wilson’s Disease
10,21
ceruloplasmin
KF rings
Ceruloplasmin
Slit lamp–KF
Liver tests
24 hr urine
Normal results
Liver tests
Cu2+ > 250 μg/g
Histology
Cu2+ = 50-250 μg/g
Histology
Cu2+ < 50 μg/g
Histology
Mutation analysis
Wilson’s disease
Treatment
Family screening
4
Other diagnosis
with >250 μg/g dry liver tissue weight providing
the strongest biochemical evidence for Wilson’s
disease and normal values (<40–50 μg/g dry liver
tissue) excluding this diagnosis.10 Typical histologic
abnormalities seen in Wilson’s disease include microand macrovesicular steatosis, glycogenated nuclei in
hepatocytes, and focal hepatocellular necrosis.10,28,29
With confirmed diagnosis of Wilson’s disease,
any first-degree relatives of the patient should also
be screened by either biochemical or genetic
testing.10 Assessment should include history and
physical examination as well as the diagnosis
recommendations outlined above.
Treatment
Chelating agents are typically recommended as the
initial treatment in patients with active or symptomatic
Wilson’s disease.10 Penicillamine is used most often,
but trientine is becoming increasingly popular as the
primary therapy. While using either chelating agent,
care should be taken to slowly increase the dose
to reach the initial target (Table 1). Combination
therapy of zinc used with a chelating agent (separated
temporally) could theoretically block copper uptake and
eliminate excess copper; however, this has only been studied
A diagnosis of Wilson’s disease should be considered in any
child over the age of 3 years who presents with unexplained
liver test abnormalities.10,22 Patients with suspected Wilson’s
disease should undergo careful slit lamp examination by
an experienced examiner to assess for the presence of
KF rings, although the absence of these rings does not
exclude diagnosis, even in patients with predominantly
neurological symptoms.10,20,23 Routine measurement of serum
ceruloplasmin is also recommended during evaluation of
unexplained hepatic, neurologic, or psychiatric symptoms,
with an extreme low (<50 mg/L or 5 mg/dL) indicative of
Wilson’s disease.10 However, normal ceruloplasmin levels do
not necessarily exclude Wilson’s disease.
In patients without both KF rings and normal serum
ceruloplasmin concentration, additional testing is necessary
to assess for Wilson’s disease. Basal 24-hour urinary
excretion of copper aids in the diagnosis of the disease.
Copper levels in an appropriately collected urine sample
>100 μg/24 hours in symptomatic patients indicate Wilson’s
disease, whereas those >40 μg/24 hours require further
investigation.10,24-26 Urine copper levels >1600 μg/24 hours
with the administration of D-penicillamine (500 mg at the start
of the collection and 12 hours into it) may provide additional
evidence for the presence of Wilson’s disease.10,27
In addition to serological and urinary testing, hepatic
copper content and histology provide important information,
5
in preliminary reports and efficacy over treatment with a
chelator alone has not yet been determined. Additionally,
ongoing studies are investigating the use of tetrathiomolybdate
as an alternative chelator for initial treatment in patients with
neurologic symptoms. Vitamin E can also be considered for
use as an antioxidant. These treatments are further detailed in
Table 1.
adherence can result in recurrent symptoms and liver failure,
which requires liver transplantation. Therefore, it is important
for the physician to monitor patients for compliance as well as
potential adverse effects of treatment.
Case Study 1: Follow-Up
Javier’s initial low ceruloplasmin concentration suggests
Wilson’s disease. He has no KF rings by slit lamp examination.
Results of a 24-hour urine copper (140 μg) and hepatic copper
content (846 μg/g dry liver tissue) are markedly elevated and
confirm diagnosis of Wilson’s disease. Javier is started on
trientine monotherapy.
Once symptoms or biochemical abnormalities stabilize
(typically 2–6 months after therapy initiation), maintenance
doses of chelators or zinc can be used, and treatment is lifelong.
Zinc monotherapy can be considered in presymptomatic
patients who are identified by family screening. Poor treatment
Table 1. Treatment Approach for Wilson’s Disease
10,30-34
Drug
Penicillamine
Trientine
Zinc
Tetrathiomolybdate
Vitamin E
Action
Dose
Adverse Effects
Chelator
Initial 20 mg/kg/day
(1.5–2 g/day) given in 2 or
3 divided doses
Maintenance
10–20 mg/kg/day
(0.75–1.5 g/day) given in 2
or 3 divided doses
Generalized pruritus
Early and late rashes
Anorexia
Gastronintestinal pain
Nausea
Vomiting
Diarrhea
Blunting, diminution, or total
loss of taste perception
Leukopenia
Thrombocytopenia
Proteinuria
Hematuria
Tinnitus
Optic neuritis
Dystonia
Chelator
Initial 20 mg/kg/day
(1.5–2 g/day) given in 2 or
3 divided doses
Maintenance
10–20 mg/kg/day
(0.75–1.5 g/day) given in
2 or 3 divided doses
Iron deficiency
Systemic lupus
erythematosus
Dystonia
Muscular spasm
Myasthenia gravis
Blocks absorption
75–150 mg/day (in 3
divided doses)
Gastric irritation
Chelator
Blocks absorption
150–200 mg/day
Anemia
Neutropenia
Leukopenia
Transaminase elevations
Antioxidant
400–1200 IU/day
N/A
6
Lysosomal Acid Lipase Deficiency
Pathophysiology
LAL deficiency presents clinically in 2 phenotypes: the
infantile-onset Wolman disease (WD) and later-onset
CESD. WD occurs in 1 in 500,000 infants, usually
between the ages of 2–4 months.35-37 In these infants,
LAL activity is absent or decreased to <1% of normal
values, causing massive lysosomal accumulation of
cholesteryl esters (CEs) and TGs, predominantly in the
liver, spleen, adrenals, bone marrow, lymph nodes, and
in macrophages throughout the body, particularly in the
intestinal villi.36,38-41 Infants present with vomiting, diarrhea,
massive hepatosplenomegaly (HSM), severe liver disease,
adrenal calcifications in 50% of cases, feeding difficulties,
malabsorption, malnutrition, and growth retardation. It often
leads to patient death by age 12 months.35,36
CESD is an autosomal recessive lysosomal storage disorder
that occurs in 1 in 40,000 people and results from mutation
in the LAL gene (LIPA) that cause marked reduction in LAL
activity.42-44 As a result, CEs accumulate throughout the body.
The degree of accumulation usually correlates with the tissues’
relative participation in receptor-mediated endocytosis and
lysosomal degradation of lipoproteins.35,42,43 Organs that
are predominantly affected are the liver, spleen, adrenals,
bone marrow, lymph nodes, and intestinal villi. Defective LAL
activity reduces hydrolysis of CEs and TGs and causes massive
sequestration, particularly in Kupffer cell and hepatocyte
lysosomes as well as other cells of the macrophage/monocyte
system. Lack of free cholesterol due to lysosomal trapping
of CEs leads to reduced feedback inhibition of 3-hydroxy-3methylglutaryl-coenzyme A reductase, which in turn leads
to increased synthesis of cholesterol and upregulation of
apolipoprotein B synthesis and LDL receptors on cell membranes.
The dysregulated expression of the LDL cholesterol–dependent
adenosine triphosphate–binding cassette transporter 1 gene
contributes to HDL cholesterol reduction.
Case Study 2: Alina
Alina is a 13-year-old girl of Polish American descent who is
referred by her primary physician for abnormal liver enzymes,
hepatomegaly, and fatty liver observed by ultrasound. She
has been previously healthy but, over the past 6 months, has
constantly felt tired. Thyroid function test results are normal.
She does not have symptoms of abdominal pain, fever,
jaundice, itching, bleeding, cold intolerance, or irregular
defecation. She has not lost or gained weight but is smaller
in size than her peers. She does not currently take any
medicine or herbal therapies and eats a typical American
diet, though she does not exercise much on a regular basis.
On physical examination, her BMI is 22 kg/m2 and she
has hepatomegaly but no signs of chronic liver disease.
Her most recent laboratory workup includes an AST level of
56 IU/L (increased from 55 IU/L 3 months earlier), ALT
level of 67 IU/L (decreased from 77 IU/L), high-density
lipoprotein (HDL) of 35 mg/dL (decreased from 40 mg/dL),
low-density lipoprotein (LDL) of 292 mg/dL (increased from
262 mg/dL), and triglyceride (TG) of 122 mg/dL (decreased from
135 mg/dL). Computed tomography of her abdomen reveals
diffuse low attenuation of liver parenchyma compatible with
fatty infiltration, and the maximum craniocaudal length of her
liver is 20 cm.
CESD may present in infancy, childhood, or adulthood,
depending on the residual in vitro LAL activity (1%–12% of
normal) and is underrecognized, especially in patients
of European ancestry and Persian Jews. It is commonly
misdiagnosed as NAFLD, nonalcoholic steatohepatitis, or
cryptogenic liver disease.42,44 It presents as hepatomegaly
and liver dysfunction and/or type IIb dyslipoproteinemia
(increase in total cholesterol [Tchol], LDL, and TG and decrease
in HDL).42,43 Liver tissue in patients with CESD is grossly
bright yellow-orange in color, and histology reveals massive
lysosomal accumulation of CEs and TGs in hepatocytes,
7
Kupffer cells, and macrophages, giving the microvesicular
steatosis picture. Progressive lipid deposition leads to fibrosis,
micronodular cirrhosis, and ultimately liver failure.
liver failure and subsequent death.57,58 Extrahepatic organ
involvement, even in transplanted patients, can result in
significant disease burden and premature death.
Diagnosis
Sebelipase alfa is currently under investigation as a potential
enzyme-replacement therapy for patients with LAL deficiency.
In preclinical trials, this recombinant human LAL enzyme
effectively reversed lipid storage in the liver, decreased lipid
concentration in key tissues, normalized liver function, and
corrected clinically relevant abnormalities, including liver size
and growth failure.43,59-61 In the first human study, 9 patients
received 4 weekly infusions of sebelipase alfa at doses of
0.35, 1, or 3 mg/kg–1.43 Patients who completed the first
treatment arm were given an additional round of treatment
before switching to long-term, every-other-week infusions of
1 or 3 mg/kg. In 7 of the 9 patients (78%), mean ALT and
AST decreased by 52% and 36%, respectively, at week 12
compared to baseline. At week 12, the same 7 patients also
had mean decreases in Tchol (22%), LDL cholesterol (27%),
and TGs (28%) and increases in HDL cholesterol (15%). Further
clinical trials for sebelipase alfa are ongoing, and enrollment
in one of these studies may be a viable option for therapy.
The rarity of LAL deficiency makes it easy to miss or
misdiagnose, but various diagnostic and screening tools are
available for appropriate diagnosis. Typical diagnosis is based
on laboratory evaluation demonstrating transaminitis and/or
dyslipidemia.44 Hepatomegaly or HSM is a common finding
on physical examination. Fatty infiltration is seen on radiological
or histological evaluation. Symptoms can be nonspecific and
include diarrhea, abdominal pain, malabsorption, or those
related to cholestasis or cardiovascular disease or early
stroke. Clinical suspicion for CESD is confirmed via genetic
testing. Over 40 loss-of-function LIPA mutations have been
identified in patients with LAL deficiency,45-54 with E8SJM
being the most common mutation. Traditional enzyme assays
for LAL activity in peripheral leukocytes, cultured fibroblasts,
or liver tissue have been used. More recently, dried blood
spot (DBS) analysis for LAL activity has become available as
a simple and more-specific assay for LAL enzyme activity,
with a good separation of the activities of normal controls
and CESD homozygotes and heterozygotes.55 It uses
4-methylumbelliferyl-palmitate as the enzyme substrate and
the LAL-specific inhibitor, Lalistat 2.
Case Study 2: Follow-Up
Alina’s elevated ALT, dyslipidemia, and fatty liver on radiology
evaluation in the absence of being overweight or obese
leads to further evaluation, including a liver biopsy and LAL
assay through DBS testing. Liver biopsy shows enlarged
hepatocytes with high lipid content, and LAL enzyme activity is
<0.02 pmol/punch/hour (normal limit 24–134 pmol/punch/hour).
Alina is diagnosed with CESD. Although there is currently no
approved therapy, ongoing trials should be monitored for a
potential avenue for treatment.
Available laboratories in the United States for DBS and LIPA
sequencing analysis are provided in Table 2.
Treatment
There is currently no approved treatment for LAL deficiency,
although liver transplantation has been effective in preventing
Table 2. US Laboratories for DBS Testing and LIPA Gene Sequencing
Laboratory
56
Contact Information
Available Test
Phone: (800) 345-4363
Web site:
www.labcorp.com/wps/portal/provider/testmenu
LAL deficiency test code: 402300
DBS
Massachusetts General Hospital,
Neurogentics DNA/Biochemical
Diagnostics Lab (Boston, MA)
Phone: (617) 726-5721
Web site:
www.massgeneral.org/research/resourcelab.aspx?id=43
DBS
LIPA
Seattle Children’s Hospital,
Biochemical Genetics Laboratory
Phone: (206) 987-2216
Web site: www.seattlechildrens.org/labman
DBS
Laboratory Corporation of America
(Research Triangle Park, NC
8
Alpers Syndrome
Pathophysiology
Alpers-Huttenlocher syndrome (Alpers syndrome)
is an inherited, monogenic, autosomal recessive
disorder that occurs in approximately 1 in 100,000
patients. It is caused by mutation of the POLG
gene,62-65 which is the sole polymerase replicating
mitochondrial DNA (mtDNA).66,67 POLG mutations
can result in a reduced number of mtDNA copies in
the muscle, brain, and liver cells, causing a decrease in
cellular energy that manifests in typical Alpers syndrome
signs and symptoms and eventually leads to fatal brain
and liver disease in children and young adults.62,63 Onset
of Alpers syndrome usually occurs in early childhood (age
2–4 years), although it can occur later.62,64,66 The typical
presentation includes 3 factors: refractory seizures including
a focal aspect, psychomotor regression (often episodic), and
liver disease.63 Additional symptoms may include ataxia and
neuropathy that can lead to areflexia.62,65,66 Affected patients
may also develop hypotonia that worsens until they can
no longer control their muscles and movement, myoclonus,
choreoathetosis, or parkinsonism. Migraines with visual
sensations or auras are common, and patients may also have
fatigue, inability to concentrate, irritability, memory loss, loss
of language skills, and eyesight or hearing loss.
Case Study 3: Jacob
Jacob is a 13-year-old Caucasian boy who presented to
the emergency department 3 months ago with uncontrolled
seizures and respiratory distress. The BMI is 20 kg/m2,
and his height, weight, and head circumference were all in
the 10th–50th percentile for his age. No dysmorphology
was noted. Jacob’s medical history showed delayed
developmental milestones, as he did not learn to walk until
age 24 months. Brain magnetic resonance imaging (MRI) at
age 4 years was normal, and an intelligence quotient (IQ) test
at age 10 years gave his IQ as 65 (verbal: 75; performance:
58). He has attention deficit hyperactivity disorder (ADHD)
including motor and verbal tics. He is the second child of
nonconsanguineous parents, and there is no family history of
gastrointestinal or liver disease. His initial workup included
an abdominal ultrasound that showed hepatomegaly with
increased echogenicity. Electroencephalography showed
generalized spikes and slow waves with focal sharp waves
in the frontal regions. A brain MRI showed bilateral signal
changes affecting the thalamus and caudate atrophy of the
frontal, cerebellar, and temporal lobes. Routine laboratory
workup including a CBC, electrolyte profile, liver enzymes,
and renal function was ordered. Sodium valproate (VPA)
was prescribed to control seizures (blood level maintained at
650–900 μmol/L). Three months later, the patient returns with
increasing fatigue and vomiting.
Patients with Alpers syndrome are at an increased risk for
fatal hepatopathy if treated with the anticonvulsant VPA, a
successful and popular first-line therapy for seizures that is
also used to treat headaches and bipolar disorder.65,68-70
This hepatopathy does not improve with discontinuation of
the drug. More than 1 in every 37,000 patients exposed
to VPA can develop liver toxicity, with the risk increasing
to approximately 1 in every 500 pediatric patients on
polytherapy.70,71 The National Institutes of Health–funded
Drug Induced Liver Injury Network studied 17 patients across
5 centers from 2004 to 2008 and found that a heterozygous
defect in POLG was strongly associated with VPA toxicity
(odds ratio 23.6).70
Diagnosis
A diagnosis of mitochondrial disease should be considered
in patients with hepatic steatosis with normal BMI; lactic
acidosis and hypoglycemia; and when associated
extrahepatic manifestations, such as neurological signs,
myopathy, and developmental delay, are present. In patients
with the standard presentation of Alpers syndrome (refractory
seizures, psychomotor regression, and liver disease with or
without failure), diagnosis can be confirmed by genotyping
9
for characteristic POLG mutations.63 A467T is the most
common mutation in POLG, followed by W748S and
G848S.63,66 Unless synthetic liver failure exists, liver biopsy
should be considered to exclude Wilson’s disease and detect
the presence of the histological criteria provided in Table 3.
Muscle biopsy may also show depletion of mtDNA in Alpers
patients but often provides normal results.66,72 Additional
criteria are provided in Table 4.
Toxic medications, such as VPA, should be eliminated
and/or avoided in treatment regimens to avoid potential liver
failure; alternatively, one may consider performing a POLG
mutation screen prior to initiating VPA if other medications
are contraindicated. In a review of clinical trials, there is no
evidence supporting the use of any treatment intervention
in primary mitochondrial disorders.74 However, antioxidant
therapies may provide symptom relief. Supplementation
with coenzyme Q has shown beneficial effects on electron
transport chain function, though its specific effectiveness and
recommended dosing have not been defined.74,75 In clinical
practice, some patients with mitochondrial diseases report
Treatment
Treatment of Alpers syndrome is based on symptoms and
patient support.73 There is no cure or means to slow progression.
Table 3. Major Liver Histological Criteria for Diagnosis of Alpers Syndrome
63
Microvesicular steatosis
Proliferation of the bile ducts
3 of the
following:
Hepatocytes dropout or focal necrosis with/without portal inflammation
Ductal plate collapse
Parenchymal disorganization or disarray of normal lobular structure
Bridging fibrosis or cirrhosis
Regenerative nodules
Oncyocytic change in scattered hepatocytes not affected by steatosis
Table 4. Minor Criteria for Diagnosis of Alpers Syndrome
63
Elevated cerebrospinal fluid (CSF) protein (>60 mg/dL)
Brain proton magnetic resonance spectroscopy showing reduction of N-acetyl aspartate,
normal total creatine, and elevated lactate in affected portions of the cerebral cortex,
basal ganglia, and thalamus
Cerebral volume loss
2 of the
following:
At least 1 electroencephalogram with asymmetric or posterior high-amplitude slow
waves (200–1000 µV, 0.73–3 Hz) mixed with lower-amplitude polyspike discharges
(10–100 µV, 12–25 Hz)
Optic atrophy or cortical blindness
Abnormal visual-evoked potentials and normal electroretinogram
Quantitative mtDNA depletion in skeletal muscle or liver
Liver or skeletal muscle polymerase γ enzyme activity ≤10%
Elevated blood or CSF lactate (≥3 mM) on at least 1 occasion with
absent acute liver failure
Isolated complex IV or combined I, III, and IV electron transport complex ≤20% of
normal on liver respiratory chain testing
Sibing with confirmed Alpers syndrome
10
improvement in muscle cramping and discomfort. Idebenone
can be an effective option for treatment of ataxia, especially
in patients with discordant visual acuities, and has been
shown to be efficacious and safe in both pediatric and adult
patients.76-78 In addition to coenzyme Q, supplementation of
various vitamins, including L-carnitine, folic acid, and creatine
monohydrate, is often used in patients with mitochondrial
disease. These natural compounds are generally considered
harmless at currently prescribed doses, but there is no specific
evidence for their efficacy outside of anecdotal reports and
recommended treatment protocols do not exist.75 In general,
systemic manifestations of Alpers syndrome preclude the option
of liver transplantation as treatment. Liver transplantation has
been attempted in VPA-induced liver failure with successful
engraftment in most cases, but these patients still died soon
after as a result of progressive neurological deterioration.65,79,80
Conversely, patients who have disease with deoxyguanosine
kinase deficiency and no central nervous system involvement
may benefit from liver transplantation.81
liver failure. The patient also shows many warning signs of
Alpers syndrome, including delayed development, uncontrolled
seizures, and inability to concentrate (previous diagnosis of
ADHD). The VPA regimen is stopped immediately to avoid
any further contribution to liver disease or hepatopathy, and a
liver biopsy is ordered. Biopsy shows microvesicular steatosis,
bile duct proliferation, and bridging cirrhosis, confirming the
diagnosis. Although there is no approved treatment for Alpers
syndrome, he is put on a trial of supplements that include
coenzyme Q and L-carnitine and monitored for symptom
improvement.
Summary
Obesity causes most fatty liver disease; however, it is not the
cause of all fatty liver disease. Other causes of NAFLD include
cystic fibrosis, Wilson’s disease, total parenteral nutrition,
diabetes mellitus, lipodystrophies, fatty acid oxidation defects,
mitochondrial hepatopathies (such as Alpers syndrome), LAL
deficiency, drug toxicity, and rapid weight loss. Clues to
NAFLD not caused by obesity include absence of obesity,
microvesicular steatosis predominance, medication and herb
exposure, clinical features other than obesity, and significant
hypercholesterolemia. It is also important to note that, whereas
these diseases are examples of nonobese causes of fatty liver
disease, it is still possible for them to occur in obese patients,
and therefore, care providers should continue to entertain
them in their differential diagnosis of NAFLD in both obese
and nonobese individuals.
Case Study 3: Follow-Up
Increased fatigue and vomiting indicate a need to evaluate
Jacob further. Additional laboratory workup is ordered, and
relevant results include an ALT of 306 IU/L, total bilirubin of
7.7 mg/dL, international normalized ratio of 2.2, ammonia
level of 123 mg/L, and lactate level of 3.9 mmol/L. The
international normalized ratio did not improve with vitamin K
repletion. These symptoms and results are indicative of acute
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14